This invention relates to a method of contraception. It has now been found that the transdermal application of the progestin analog ST1435 to the skin (hereinafter "topical application") is effective in attaining therapeutically effective serum levels of ST1435.
The most common form of hormonal contraception is oral contraceptives, which are widely popular as one of the most effective means of contraception available. Oral contraceptives usually contain a combination of the hormones estrogen and progestin. Unfortunately, natural hormones and many synthetic hormones are unsuited to oral administration. Most hormones suffer some degradation in the digestive tract and many are rapidly degraded by the liver in the so-called hepatic first-pass metabolism. Since even synthetic hormones may be metabolized to some extent during absorption, a large excess of hormone is frequently administered. Decreasing the dosage of hormones would have the effect of decreasing the risk of side effects but would decrease the efficacy of the hormones. A synthetic estrogen such as ethinylestradiol is ordinarily used as the estrogen component in oral contraceptives since less than ten percent of the natural estrogen, 17-.beta.-estradiol, survives hepatic first-pass metabolism. In contrast, approximately 40% of ethinylestradiol survives hepatic first pass metabolism. Likewise, natural progesterone is ineffective when given orally except in micronized form and in large doses. Additionally, many synthetic hormones are unsuited to oral administration; for instance, the synthetic progestin ST1435 (16-methylene-17-.alpha.-acetoxy-19-nor-4-pregnene-3,20-dione) is ineffective when given orally due to rapid first-pass metabolism.
In order to circumvent hepatic metabolism, methods of hormone administration involving implants and topical applications have been developed. A typical implantable device is described in U.S. Pat. No. 3,854,480 issued Dec. 17, 1974 to Zaffaroni. Such a device consists of an inner core within which solid particles of drug are dispersed and an outer membrane that surrounds the inner core. The inner core is relatively permeable to the hormone and the outer membrane is relatively impermeable. The outer membrane thus regulates the rate of hormone delivery from the implant. Such implants are normally placed under the skin and have the advantage of prolonged drug release at a controlled rate.
The feasibility of a topical delivery system for contraception was realized when it was shown that testosterone, testosterone conjugates and estradiol could be absorbed through the skin. Topical delivery of contraceptive steroids has potential advantages over some of the present contraceptive dosage forms that are available to the public. Such advantages include: convenience of application and removal by the user; avoidance of hepatic first-pass metabolism and gastrointestinal incompatibility; controlled sustained release of the contraceptive drugs; maintenance of a steady-state plasma level of the drug(s), resulting in enhanced efficacy; and reduced frequency of dosing, as compared to daily oral contraception.
The advantages of topical administration of steroids have been widely acknowledged in recent years. Estradiol is used routinely in commercial preparations for the relief of postmenopausal symptoms. Whitehead et al., "Endometrial Responses to Transdermal Estradiol in Postmenopausal Women", Am. J. Obstet. Gynecol., 152:1079-1084 (1985). It has also been shown that transdermally administered testosterone is effective in long-term treatment of male hypogonadism. Ahmed et al., "Transdermal Testosterone Therapy in the Treatment of Male Hypogonadism", J. Clin. Endocrinol. Metab., 66:546-551 (1988).
Known topical applications for hormones are comprised of hormone dissolved or suspended in any of several liquid, semisolid, or solid vehicles. Liquid and semisolid vehicles have heretofore been used for therapeutic but not contraceptive administration of hormones. Such vehicles include but are not limited to gels, creams, ointments and rinses in which the hormone is at least somewhat soluble. A hormone should be at least partially soluble in the vehicle to facilitate delivery. Solid vehicles containing hormones are available, such as the "patch" described in U.S. Pat. No. 4,818,540, issued Apr. 4, 1989 to Chien et al. Such a transdermal device consists of the following elements: a backing layer relatively impervious to the hormone; a polymer matrix disk layer in which the hormone is dispersed; and an adhesive layer that adheres the device to the skin and allows the hormone to be absorbed transdermally.
Topical applications generally require administration of a lower concentration of the hormone than do oral dosages and are relatively easy to apply. Transdermal devices are useful for several days before the device must be changed. However, use of such devices for more than a few days in one location results in irritation and may cause dermatitis due to occlusion of the skin. The efficacy of transdermal applications is also determined in part by the thickness of the stratum corneum and hydration of the skin which affect diffusion of steroids through the skin, Sitruk-Ware, "Innovative Technology for Hormonal Replacement Therapy", Maturitas, 10:79-81 (1988).
Skin occlusion is a serious drawback to the use of transdermal patches. Occlusion occurs when the skin is blocked so that the passage of any gases or moisture through the skin is prevented.
Occlusion of the skin for the short term (a few days) is not harmful and may be helpful in some transdermal applications. However, over the long term (i.e., more than a few days) occluded skin becomes "macerated", that is the skin breaks down and becomes susceptible to infections, especially fungal. It would be advantageous to find a drug delivery system capable of delivering or a drug capable of being delivered transdermally without occlusion of the skin.
Many hormones, most notably progesterone, are not amenable to transdermal administration; due to low skin penetration high steroid dosages are necessary to maintain adequate blood levels. Sitruk-Ware et al, "Treatment of Benign Breast Diseases by Progesterone Applied Topically", In: Percutaneous Absorption of Steroids, Mauvais-Jarvis, et al., eds. London, England: Academic Press, pp. 219-229 (1980). The efficacy of natural progesterone is further decreased by its conversion in the skin to 5-.alpha.-dihydroprogesterone by 5-.alpha.-reductase. Mauvais-Jarvis et al., "In vivo Studies on Progesterone Metabolism by Human Skin", J. Clin. Endrocrinol. Metab., 29:1580-1585 (1969).
It has now been found that, unlike natural progesterone, topically applied synthetic progestin ST1435 diffuses through the skin to achieve pharmaceutically effective serum levels. This is unexpected since ST1435 is similar to progesterone in being degraded during hepatic first-pass metabolism and was consequently expected to be enzymatically degraded by 5-.alpha.-reductase in the skin. Topical application of ST1435 is thus suitable for contraception and any other indication for which ST1435 is an effective hormonal treatment. Furthermore, as shown in the examples provided below, ST1435 can be delivered transdermally in therapeutically effective amounts without occluding the skin.